Hydroxy alkyl xanthines and the production thereof



Fatentecl Aug. 1, 1950 HYDROXY ALKYL XANTHINES AND THE PRODUCTION THEREOF Viktor Papesch, Morton Grove, Ill., assignor ,to G. D. Searle & 00., Skokie, 111., a corporation of Illinois No Drawing. Application August 15, 1947,

SerialNo. 768,929

This invention relates to xanthines containin hydroxyalkyl substituents, and to processes for preparing the same. It particularly relates to hydroxyalkyxanthines of the following general formula:

R-N-CO R wherein one B, is hydrogen, one B is a hydroxyabkyl radical and the third R and R are members of the group consisting of hydrogen, hydroxyalkyl and alkyl radicals.

For many years, the naturally occurring methylated xanthines, theophylline, theobromine and cafieine, have found wide use in therapeutics. Generally speaking, the two dimethyl compounds, theophylline and theobromine, have somewhat similar therapeutic utility in that both are used primarily as vasodilators and diuretics, with little if any central stimulating action. When a third methyl group is introduced, forming carfeine, the action is changed so that the com-' pound is primarly a central stimulant. Any re-' sidual vasodilator or diuretic properties which caffeine may have are unavailable for practical use inasmuch as any dose large enough to ex-' hibit such properties will at the same time exhibit undesirably great central stimulating properties.

In the xanthine molecule, there are three nitrogen atoms (conventionally numbered 1, 3 and 7) to which are attached salt-forming (or acidic) hydrogen atoms, which hydrogen atoms are capable of being replaced by alkyl or substituted alk-ylgroups, When such groups are introduced in place of the hydrogen atom, thesalt-forming properties inherent in that portion of the mole cule vanish. Thus a monoalkyl xanthinehas two such salt-forming hydrogen atoms left in the molecule; dialkyl xanthines (of. which theophylline and theobromine are examples) have one salt-forming hydrogenwhile trialkyl xanthines, such as caffeine, have no salt-forming properties at all. In an attempt to improve the properties of theophylline and of theobrornine, earlier, workers have introduceda hydroxyethyl group onto the remaining unsubstituted nitrogen atom in these molecules, resulting in the formation of '7- beta-hydroxyethyl-1,3-dimethylxanthine and lbeta-hydroxyethyl-3,7-dimethylxanthine respectively. However, such substitution immediately changes the nature of the compound from a disubstituted. salt-forming theophylline-like com- 10 Claims. (01160 -256) 2 pound to a tri-substituted, neutral cafieine-lik compound.

I have now found in this invention that useful and improved therapeutic compounds can be obtained by preparing hydroxyalkylxanthines.

which resemble theophylline or theobromine in that they contain at least one unsubstituted nitrogen atom with itssalt-forming hydrogen atom, but in which at least one of the alkyl groups substituted on the remaining nitrogen atom. has one or more hydroxyl groups.

In the compounds of the above general formula, one R. represents a hydroxyalkyl radical wherein at least 2 carbon atoms separate the hydroxyl group and the nitrogen atom of the xanthine ring. Among the preferred substances are those containing in the 3-position a betahydroxyethyl radical. Other hydroxyalkyl substituents are suitable, among them being betahydroxypropyl, beta gamma-dihydroxypropyl, gamma hydroxypropyl, gamma-hydroxybutyl, beta-hydroxybutyl and related substituents. The aliphatic radicals represented by R andR' include the lower alkyl radicals such as methyl, ethyl, propyl, butyl, amyl and their isomers, as well as monoand polyhydroxyalkyl radicals such as those discussed hereinbefore.

The compounds to which this invention relates maybe used in the form of the free xanthine or they may be converted to suitable salts With organic amines such as ethanolamine, diethanolamine, ethylenediamine, isopropylamine, diethylaminoethanolamine, diethylamine and the like. They may, also be used in, the form of their esters with aliphatic acids such as the lower iattyacids.

My invention is further disclosed by the following examples, which are intended only as illustrations and which in no way limit my lnven tion in spirit or in scope.

Example 1 ter anddissolved in 300 cc. of warm water containing 40-50 g. of calcium oxide. The resultin mixture is refiuxed .for 2 hours. The mixture is acidified with concentrated hydrochloric acid and cooled. The precipitate of 3-beta-hydroxyethylxanthine is collected on a filter, washed and recrystallized from water, using decolorizing charcoal. The product thus obtained melts at about 290-292 C. (uncorrected) and has the formula H-N-CO H Example 2 25 g. of 3-beta-hydroxyethyl-4,5-diaminouracil and 200 cc. of acetic anhydride are refluxed for 2 hours. The mixture is cooled and filtered, The precipitate is washed by suspension in 100 cc. of water and filtration. It is then recrystallized from 500 cc. of water, using decolorizing charcoal (melting point about .283-285f C,.', uncorrected) The 3-beta-hydroxyethyl-8-methylg an: thine acetateso obtainedis then refluxed with an .excesscf calcium oxide for about 6 /2 hours. Upon neutralization of thesolution, 3-beta-:hyv droxyethyl-8emethylxanthine precipitates. After recrystallization ,from water it .melts at about 335 C. (uncorrected). It has the formula HN'o0 H o N l T.\C-CH: no-on'r'onrr Example 3 200 g. of 3-beta-hydroxyethyli-aminouracil are dissolved in 60 cc. of 50% sodium hydroxide solution and 600-700 cc. of water. The solution is stirred While 1'27 cc. of dimethyl sulfate are added in portions Near the end of the aol'dit'i'on the mixture heats itself to till-100 C. 'and ha's to be cooled before the rest of the di-meth'yl sulfate is added. Then a small amount of alkali is added to make the mixture Weakly alkaline. When the addition is complete the mass is cooled and filtere'cl. The filter cake is washed by suspension in ice water and filtration. I A

120 g. of 3-beta hydroxyethyl-l-metliyl aminouracil in l liter-0f water'are 'nitro'sated by the addition of 45 g. of sodium nitrite, boiling and then the addition of 45 cc. of glacial acetic acid. The charge is heated for a few minutes. on chilling, a precipitate of the 'nitros'o compound forms which is collected on a filter. V

Into 224 cc. of 28% ammo'niu'in hydroxide and 450cc. of ice is passed hydrogen sulfide until the uptake is 55 g. The solutidn 'is then heated to boiling and 1'12 g. of the above nitroso compound are added in small portions. The r nixture is boiled for 2 hours, then filtered the aid of decolorizing charcoal {The filtrate is evaporated on the steam bath ohm nearly dry. There is obtained inthis way crystalline 1-methyl-3- beta-hydroxyethyl-klfi-diaminouraci1.

9.8.5 g. of the.above compound are refluxed with 400.. cc. of vformicacid for .3 hours. .The formic acid is then removed by. vacuumdistillationand the residueis taken up. in about 1 liter of Water... The mixture is filteredto remove sulfur-and 90 g. of calcium oxideare added to the filtrate. The .;s uspension is.boiled..f0r 2 hours. The resulting .solutioniamade slightly acid with concentrated. ,hydrochloric acid. and. a precipitate forms. The charge is chilled andfiltered. The l-methyl-3-beta-hydroxyethylxanthine is.

4 washed with Water and dilute alcohol, and then recrystallized from water with the aid of decolorizing charcoal. The product thus obtained melts at about 279 C. (uncorrected) and has the formula CH3N--C0 .H

Example 4 is obtained 3,7-di-beta-hydroxyethy1xanthine of M. P. about 214-216 C. (uncorrected). It has the formula H-N-O o CHaCHaOH s o 3.- e whyslms sth leez i m nom il, and..30 f pr piq m anh r d amin s: ouehl mix u i s ol daild h n. t dlq r fl for ho rs Thw re ise ledaw filt re sam e o e. s id cr sak o 3-bta-h drox hy -eth eininc, r omfi s. r s l ze ite water. .fiun o ee d. .1 out 2 and than th te tis usp n ed li tw onwh' chen x s oi a cium. ide cad 'e The. mi t r isb 'i d. o hou s. an

'- he n elizedwi h minera id. .Thepreq ir bate. p 0 -h dr x et Feili xaet in is co ected. on aer.. e st l eed fro at and melts at about 340 C. (uncorrected). It has the formula emcmc iait Ls Example 6 2o jg. cr 3 beta-hydrokyethylkanthine were ple 1]), 60 cc. of 1Q% 'so'dium hydroxide and IQO cc. of water are warmed to effect solution, then cooled to 45 C. and stirred while 15 g. oi dirnethyl sulfate are addedfdropwise in 2Q min utes. The charge ish'e'ated to (3., treated with decolor'izing charcoaL filtered a cooled to 20 2, Dilutefinineral acjidfi's jadded tb ne tralize the :filtr'ate, and 'crystallization ensues. The mass is chilled thoroughly and then filtered. The '3-beta-hydroxyetliy157-:methylxanthinethus isolated is recrystallized from water with the use of a filter aid and melts at about 245 C. (uncorr'ecte'd). Ithas the formula 'H-t o'o cm at (LN .'...l..;:.:' HO--CHiCH2N-C-N Example 7 22.7 g. of 3-methylxanthine in 55 cc. of 10% sodium hydroxide and 110 cc. of water are heated at 90l00 C. with 18 g. of glycerol monochlorohydrin for about 2 hours. The reaction mixture is filtered. The filtrate is evaporated and the residue is collected on a filter and washed with a small amount of cold water and then dissolved in 700 cc. of alcohol. The solution is boiled with decolorizing charcoal, chilled, filtered, concentrated and chilled. The precipitate of 3-methyl- 'l-beta,gamma-dihydroxypropylxanthine is recrystallized from alcohol and melts at about 286- 288 C. (uncorrected). It has the following formula H-N-oo CHzCHOHCHzOH H 0- CH3N' N Example 8 CHBCHiOH 10 g. of l-methylguanine are dissolved in 30 cc. of 10% sodium hydroxide and heated in a sealed tube at about 125 C. with 5.5 g. of ethylene chlorohydrin for 2 hours. The precipitate which forms is removed by filtration and recrystallized twice from water, using decolorizing char coal. The 1-methy17-beta-hydroxyethylguanine is dried at 140 C. and melts at about 250 C. (uncorrected) with sintering from about 225 C. It has the formula OHzCHzOH /CH r N/ Example 10 '70 g. of 3-methyl-4-aminouracil and 60 g. of ethylene chlorohydrin are heated together in a closed vessel at 120 C. in the presence of 30 g. of sodium hydroxide in 500 cc. of water for 2 hours. The charge is filtered and the filter cake is washed with water and dried. The solid 1- betahydroxyethyl-3-methyl-4-aminouracil thus obtained is recrystallized from water with the aid of activated charcoal. It melts at about 270272 C. (uncorrected).

51 g. of 1-beta-hydroxyethyl-3-methyl-4- aminouracil is nitrosated by solutionin 500 cc. of boiling water, followed by addition of 19 g. of sodium nitrite and 18.2 cc. of glacial acetic acid. The resulting mixture is cooled and filtered to remove the 1 -beta-hydroxyethyl-3-methyl-4- amino-S-nitrosouracil, which is washed with water and dried.

A mixture of cc... of.28% ammonia water and. 200g. of ice istreated withhydrogen sulfide until 25 g. are taken up. .Tothis solution. are added 50 g. of the above nitroso compound. After the addition, the mixture is boiled fortwo hours, then filtered and evaporated. The residueof 1- beta-hydroxyethyl-3-methyl 4,5 diaminouracil obtained by this procedure is heated with 170 cc. of formic acid until dissolved. The hot mixture is treated with charcoal and filtered. The filtrate is refluxed for 2% hours. The solution is evaporated in vacuum. The hot solution is diluted with 150 cc. of hot water, treated with charcoal and filtered. 30 g. of calcium oxide are added to make the mixture strongly alkaline, and the resulting solution is boiled 3 /2 hours. During this boiling period sufiicient calcium oxide (about 10 g.) is added to maintain alkalinity. The cooled solution is brought to pH 4 with hydrochloric acid, cooled with ice, and allowed to crystallize. The crystals of l-beta-hydroxyethyl-B- methylxanthine areremoved by filtration and recrystallized from water, using activated charcoal. The compound melts at about 235-245 C. (uncorrected) and has the formula onrn -o -n Example 11 9.8 g. of 3-beta-hydroxyethylxanthine and 6.6 g. of glycerol monochlorohydrin are heated together with 24 cc. of 10% sodium hydroxide and 24 cc. of water at -130 C. for 4 hours in a pressure vessel. The mixture is filtered and evaporated on a steam bath, then under vacuum. The residue is extracted repeatedly with hot absolute alcohol and allowed to crystallize. The crystalline precipitate of 3-beta-hydroxyethyl-7- beta,gamma-dihydroxypropylxanthine which is obtained by evaporation of the reaction mixture is removed by filtration, recrystallized twice from about 300 cc. of 95% alcohol with the aid of decolorizing charcoal, and dried at 65 C. in vacuum. It has the formula H--NOO CHrCHOHCHaOH I claim:

1. A xanthine having attached to its nitrogen atoms in positions 1, 3 and 7 not more than two hydroxyalkyl radicals and at least one hydrogen atom.

2. A hydroxyalkylxanthine having the formula 7 wherein a" is a hy'droxyalkyl radical, one a is hydrogen, and the other R and R," are members of the group consisting of hydrogen, hydroxy alkyl and alkyl radicals.

4'; A 3 beta-hydroxyethylxanthine having the formula no omcm-re-oas wherein R is a member of the group consisting of hydrogen; hydroxyalkyl and alkyl radicals.

6. 1 methyl 3 beta hydroxyethylxanthine, which has the formula.

5 Number 8 7. 3-beta-hydroxyethylxanthine, which has the formula H-N-CO H 0 1 N/ \OH HOCH2CH2-NCN 8. The process of preparing a hydroxyalkylxanthine which comprises heating a 4,5-diaminouracil having at least one nitrogen atom substituted with a hydroxyalkyl radical with an alkanoic acid, hydrolyzing the product so obtained with an inorganic base, and precipitating the hydroxyalkylxanthine with acid.

9. The process of preparing a E-beta-hydroxyethylxanthine which comprises heating a 3-betahydroxyethyl-4-,5-diaminouracil with an alkanoic acid, hydrolyzing the product so obtained with an inorganic base and precipitating the 3-betahydroxyethylxanthine with acid.

10. The process of preparing l-methyl-B-betahydroxyethyixanthine Which comprises heating l-methyl-3-beta-hydroxyethyl-4,5-diaminouraci1 with formic acid, hydrolyzing the product thus formed with aqueous calcium hydroxide and precipitatiiig the l-methy1 3-beta-hydroxyethyl- 'Xanthine with mineral acid.

VIKTOR PAPESCH.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date 

2. A HYDROXYALKYLXANTHINE HAVING THE FORMULA 